Adenosine A2A and A3 Receptors as Targets for the Treatment of Hypertensive-Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) and hypertension are prime causes for end-stage renal disease (ESRD) that often coexist in patients, but are seldom studied in combination. Kidney adenosine levels are markedly increased in diabetes, and the expression and function of renal adenosine receptors are altered in experimental diabetes. The aim of this work is to explore the impact of endogenous and exogenous adenosine on the expression/distribution profile of its receptors along the nephron of hypertensive rats with experimentally-induced diabetes. Using spontaneously hypertensive (SHR) rats rendered diabetic with streptozotocin (STZ), we show that treatment of SHR-STZ rats with an agonist of adenosine receptors increases A2A immunoreactivity in superficial glomeruli (SG), proximal tubule (PCT), and distal tubule (DCT). Differently, treatment of SHR-STZ rats with a xanthinic antagonist of adenosine receptors decreases adenosine A3 immunoreactivity in SG, PCT, DCT, and collecting duct. There is no difference in the immunoreactivity against the adenosine A1 and A2B receptors between the experimental groups. The agonist of adenosine receptors ameliorates renal fibrosis, probably via A2A receptors, while the antagonist exacerbates it, most likely due to tonic activation of A3 receptors. The reduction in adenosine A3 immunoreactivity might be due to receptor downregulation in response to prolonged activation. Altogether, these results suggest an opposite regulation exerted by endogenous and exogenous adenosine upon the expression of its A2A and A3 receptors along the nephron of hypertensive diabetic rats, which has a functional impact and should be taken into account when considering novel therapeutic targets for hypertensive-diabetic nephropathy.

A1 and A2A adenosine receptors play a protective role to reduce prevalence of autoimmunity following tissue damage

“…In accordance with our expectations, mice were rapidly ill, as shown in our T1DM model and as shown in the work by Zhang et al in mice with lupus nephritis (23). In recent studies, Patinha et al used the model of STZ in rats and also showed that agonist for A 2A R has a protective role in kidneys in hypertensive diabetic nephropathy (45,46). T1DM was shown to modify the expression of adenosine receptors in the brain and alteration in the balance of A 1 R and A 2A R also effects locomotor activity (47).…”

Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease

“…Recently, Patinha et al. demonstrated that the decrease in plasma glucose, reduction in proteinuria, and improvement in renal fibrosis in diabetic mice may be associated with the upregulation of A2aAR, which may serve as a promising therapeutic target for hypertension-DKD ( 88 ). Furthermore, the absence of A1AR does not influence the effect of TGF changes on the activation of the A2aAR on the efferent arterioles ( 31 ).…”

Pharmacological Tuning of Adenosine Signal Nuances Underlying Heart Failure With Preserved Ejection Fraction

“…In a model of hypertensive-diabetic nephropathy using spontaneously hypertensive rats treated with streptozotocin, the enzymatically-stable adenosine analogue, CADO, improved glucose metabolism (decreased hyperglycaemia and glycosuria), renal function (decreased proteinuria), and renal fibrosis (decreased glomerular collagen deposition), along with decreased renal oxidative stress ( Table 2 ) ( Patinha et al, 2020 ); authors implicated renal A 2A AR activation in these findings, given that overexpression of this receptor, but of A 1 AR and A 2B AR, was observed in superficial glomeruli and proximal and distal tubules of these animals’ kidneys ( Patinha et al, 2020 ). The hypertension-inducing adenosine receptor antagonist, 1,3-dipropyl-8-sulfophenylxanthine, aggravated renal fibrosis, but did not alter the global metabolic status and renal function.…”

“…The hypertension-inducing adenosine receptor antagonist, 1,3-dipropyl-8-sulfophenylxanthine, aggravated renal fibrosis, but did not alter the global metabolic status and renal function. This probably results from the selective preservation of tonic A 3 AR activation, given that downregulation of this receptor is considered protective against renal fibrosis ( Patinha et al, 2020 ). Taken together, these results emphasize the protective role of adenosine in hypertensive-diabetic nephropathy through dynamic expression of its receptors, which may be fine-tuned by A 2A AR upregulation and A 3 AR downregulation, thus prompting for a novel therapeutic target for this disease conditions ( Patinha et al, 2020 ).…”

“…The same occurs regarding the least expressed A 3 AR in the heart ( Table 3 ) ( Borea et al, 2018 ). The A 3 AR may be cardioprotective against reperfusion ( Ge et al, 2010 ; Hussain et al, 2014 ; Tian et al, 2015a ) by promoting angiogenesis ( Hinze et al, 2012 ), but it may aggravate pathological structural changes in the heart ( Lu et al, 2008 ) and kidney ( Patinha et al, 2020 ).…”